利多卡因通过激活AMPK/SOCS3信号通路改善阿霉素引起的急性心肌损伤

Lidocaine improves acute myocardial injury induced by Doxorubicin through activating AMPK/SOCS3 signaling pathway

目的:研究利多卡因(lidocaine,Lido)对阿霉素(doxorubicin,Dox)引起小鼠心脏损伤的治疗效果及作用机制。方法:32只SPF小鼠随机分为Saline组、Dox组、Dox+Lido组、Lido组4组(n=8),观察并检测各组小鼠体重、生存率、多普勒血流成像、心电图、心脏超声,以及血浆肌酸激酶同工酶(creatine kinase-MB,CK-MB)、肌钙蛋白I(cardiac troponin I,cTnI),心肌组织中组织因子(tissue factor,TF)、基质金属蛋白酶9(matrix metalloprotein 9,MMP-9)、磷酸化磷酸腺苷活化蛋白激酶(phosphorylated adenosine 5’-monophosphate-activated protein kinase,p-AMPK)、缝隙连接蛋白(connexin43,Cx43)、细胞因子信号转导抑制因子3(recombinant suppressors of cytokine signaling 3,SOCS3)的含量。结果:与Saline组比较,Dox组小鼠体重、生存率明显降低,心率降低、QRS波时限及QT间期延长,血浆CK-MB、cTnI值明显上升,心脏挛缩,心腔变小,TF、MMP-9升高,心脏组织中p-AMPK、SOCS3、Cx43表达减低;与Dox组相比,Dox+Lido组小鼠体重、生存率增加,心率上升,QRS波时限及QT间期正常,血浆CK-MB、cTnI值处于正常区间,心脏大小未见明显改变,TF、MMP-9降低,心脏组织中p-AMPK、SOCS3、Cx43表达增加。结论:利多卡因能通过激活p-AMPK/SOCS3/Cx43信号通路和抑制TF/MMP-9高表达改善阿霉素诱导的急性心肌损伤。

Objective:To study the therapeutic effect and mechanism of Lidocaine(Lido)on cardiac damage(Doxorubicin)in mice.Methods:Thirty-two SPF mice were randomly divided into four groups(n=8):saline group,Dox group,Dox+Lido group,and Lido group.The observation and detection of body weight,survival rate,Doppler flow imaging,ECG,cardiac ultrasound,plasma creatine kinase isoenzyme(CreatineKinase-MB,CK-MB),Troponin I(Cardiac troponin I,cTnI),tissue factor(TF)in the myocardial tissue,matrix metalloproteinase 9(MMP-9),phosphorylated adenosine 5’-monophosphate-activated protein kinase(p-AMPK),gap junction protein(connexin43,Cx43),inhibitor of cytokine signaling 3(recombinant suppressors of cytokine signaling 3,SOCS3)content.Results:Compared with the saline group,the mice in the Dox group showed the decreased body weight and survival rate,reduced heart rate,limited QRS wave time,prolonged QT interval,cardic contracture,small cardiac cavity,and increased expression of plasma CK-MB and cTnI but decreased expression of p-AMPK,SOCS3 and Cx43.Compared with the Dox group,mouse weight,survival rate and heart rate were increased in the Dox+Lido group.Moreover,the QRS wave time and the QT interval as well as the plasma expression of CK-MB and cTnI were normal in the Dox+Lido group mice.Also,no significant changes in cardiac size were observed.The expression of TF and MMP-9 decreased,but p-AMPK,SOCS3 and Cx43 levels increased in the heart tissues of the Dox+Lido treatedmice.Conclusion:Lidocaine can alleviate acute doxorubicin-induced cardiac injury through activation of the p-AMPK/SOCS 3/Cx43signaling pathway and inhibiting the high TF/MMP-9 expression.